PROJECT SUMMARY: We have previously shown that achaete-scute homolog 1, a proneural basic helix-loop-helix transcription factor, is critical for pulmonary neuroendocrine cell development and to the growth of neuroendocrine lung tumors. We postulated that achaete-scute homolog 1-defined cells might be progenitors, and have traced their fate during development and injury repair in genetically engineered mice. These progenitors were suggested to be the target population for transformation into the most common and virulent of all neuroendocrine tumors: small cell lung cancer whose precursor lesions have remained unknown. In humans repeated injury and repair in smokers lungs is an integral part of carcinogenesis. As a result, almost all human small cell lung cancers have alterations in the cancer suppressor genes Rb1 and p53. We were able to specifically delete both genes in achaete-scute homolog 1-defined neuroendocrine progenitors using the achaete-scute homolog 1 promoter. We have now demonstrated that these genetically-engineered animals have greatly reduced life span due to multiple neuroendocrine tumors. All mice show neuroendocrine cell hyperplasias or small tumors in the lungs and massive pituitary tumors derived from intermediate lobe (cause of early death). In addition we found pancreatic neuroendocrine tumors derived from glucagon-producing cells as well as pheochromocytomas (tumors of adrenal medullary tissue). In conclusion, this mouse provides an excellent model to share the light how early stages of small cell lung cancers will develop.The significance of our research is that it will directly contribute to solving the biggest need ( ie. generating in vivo models for human small cell lung cancer) that was identified in the most recent NCI's state of the art conference on human small cell cancer that has remained one of the most recalcitrant cancers over three decades.